A major focus of the current grant is an investigation of the mechanisms of immunosuppression associated with human disease. Since prostaglandins (PGs) have been implicated as a regulator of tumor growth and immune responsiveness in mice and humans, the effect of various PGs on human natural cytotoxicity (NK activity) was investigated. At very high concentrations of PG (10-6M),suppression was seen with PGE2, PGA2, and PGF2. At physiological concentrations, suppression was seen only with PGE2 and PGD2. Preincubation experiments indicated that the suppression was directed at the effector cell rather than the target cell. Moreover, the suppressive effects of supernatants obtained from a tumor cell line (PY3T3) could be attributed to PGE2. To further elucidate the increased sensitivity of T versus B lymphocytes to PGE-mediated suppression, various lymphoid cell suspensions were assessed. The results suggest that high protein kinase activity is characteristic of T cells and may be related to their higher sensitivity to cAMP agonists in comparison to non-T cells. We have completed some further studies on the phenotype of disease-associated suppressor cells and NK effector cells and have recently studied NK function in cancer patients and patients with systemic lupus erythematosus, and have found that the depressed NK activity in lung cancer patients can be correlated with the extent of tumor spread. The suppression is not related to an impairment of tumor-effector cell conjugate formation. Depressed NK function in SLE is related to disease activity. Again, this suppression was not related to an impairment in the formation of tumor-effector cell conjugates; however, interferon enhancement is defective in SLE patients. We are currently investigating if this type of disease-associated NK suppression is related to defective NK precursor cell recruitment. Specific goals for the coming year are: to determine the mechanisms by which NK function is impaired in some patients with cancer and other human disease; to determine if environmental agents which are associated with a high risk of lung cancer, such as cigarette smoking or random gas exposure in the case of uranium miners, can be associated with a suppression of NK activity; to determine if there is genetic basis for the impairment of NK activity in some cancer patients; and to characterize several hybridoma antibodies which have been developed in our laboratory which are reactive with monocyte subsets and large granular lymphocytes.